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Cancer Immunotherapy:

Promises and Challenges

David B. Page, MD

Medical Oncology

PMG East Hematology & Oncology

Earle A. Chiles Research Institute

Portland, Oregon

Disclosures

Consulting: Celldex, Nektar, Nanostring, Endopredict

Research: IRX Therapeutics, Merck, BMS, Medimmune

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The Immune System to treat cancer?

The Immune System to treat cancer?

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The Immune System to treat cancer?

Adams S, et al, JCO 2014

Stage I-III Triple Negative Breast Cancers

The Immune System to treat cancer?

Adams S, et al, JCO 2014

Stage I-III Triple Negative Breast Cancers

0% Lymphocytes

70% 5-yr Survival

50% Lymphocytes

90% 5-yr Survival

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Agenda

• FDA approved immunotherapies & how they work

• Toxicity management of immunotherapy

• Future directions

Selected Immunotherapy Approvals

1998 2010 2011 2015

Trastuzumab

IL-2

Ipilimumab

Sipuleucel-T T-VEC

2016

Blinatumomab

2014

Nivolumab Ipi+Nivo

“Immune checkpoint antibodies”

2017

CAR T-cell

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Classes of Immunotherapy: Antibody Therapy

Example: Trastuzumab

Metastatic

• Increase median survival from

20.3mo to 25.1mo

Early Stage

• Reduce recurrence rate by 36%

Hudis C, et al, NEJM 2007

ADCC

Wikipedia, ADCC, accessed 5/29/2017

Rituximab Daratumumab Cetuximab

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Classes of Immunotherapy: Cytokine therapy

Example: high dose IL-2 ���� “go for the gold”

• IV high dose cytokines in 5d. Cycles, up-titrated to toxicity

• Complete response rate: 5%; partial response rate: 10%

Atkins MB, et al, JCO 1999; Alva A, Cancer Immunol Immunother 2016

Th1 versus Th2 T-cell responses

Bailey SR, Front Immunol 2014

Suppresses

Tumor immunity

Immune

HomeostasisAnti-tumor

Autoimmunity

Extracellular

pathogen defense

Less anti-tumor

?

IL-2

IL-2

IL-2

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Classes of Immunotherapy: Vaccine Therapy

Example: Sipuleucel-T

• Metastatic Prostate Cancer

• Survival: 25.8 v. 21.7mo

• No change in tumor growth

• $100k = 259k/life year?

Di Lorenzo G, et al, Nature Reviews in Clinical Onc 2011; Kantoff PW et al, NEJM 2010

Vaccine = exogenous tumor

antigen

• Peptide / carbohydrate

• DNA/RNA, vector

• Cellular

Antigen Presentation

Wikipedia, Antigen Presentation, Accessed 5/29/2017

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Classes of Immunotherapy: Antibody conjugates

Example: Blinatumumab

• ALL (B-cell leukemia)

• Survival 7.7mo, v 4.0mo for chemotherapy

• May also eradicate minimal residual disease

Kantarjian H, et al. NEJM 2017

Leukemia

(ALL)

CD19 Cytotoxic

T-cell

CD3

Genetic Engineering of Antibodies

Bassan R, et al, Blood 2012

Bispecific antibody

BITE “Bispecific T-cell engager”

Blinatumumab

Antibody drug conjugate

T-DM-1 = trastuzumab + chemo

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Classes of Immunotherapy: Immune Checkpoint Antibodies

Larkin J et al, NEJM 2015; Littleton MJ et al, JCO 2000

TemozolamideDTIC

Classes of Immunotherapy: Immune Checkpoint Antibodies

Larkin J et al, NEJM 2015; Littleton MJ et al, JCO 2000

TemozolamideDTIC

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Immune Checkpoints

Page DB et al, Oncologist 2016

Classes of Immunotherapy: Immune Checkpoint Antibodies

Melanoma

NSCLC

RCC

Bladder Ca

Hodgkin’s Lymphoma

Merkel’s Cell

HEENT Ca

MSI-High Colorectal

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Classes of Immunotherapy: Oncolytic Viruses

Example: T-VEC

• Metastatic Melanoma

• Survival: 23.3 v. 18.9mo

• Responses in injected, non-

injected, and viscera

• Viral vector (HSV1)

• Replicate and lyse injected

tumor

• Manipulate genome to

enhance effect: - suppressive

genes; + GM-CSF

Andtbacka R, et al, JCO 2015; Amgen website, accessed 5/29/2017

CAR T-cell Therapy: Tisagenlecleucel

Maude S, et al. NEJM 2014

T-cell

ALL cell

CD19

T-cell

ALL cell

CD19

Pediatric ALL Response

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Adoptive T-cell therapy

Tumor sample

DNA sequencingIdentify somatic

mutations

Isolate and grow T-

cells that react to

mutation

Re-infuse into patient

Tran E et al, Nature Immunology 2017; Tran E et al, NEJM 2017

Agenda

Types of immune-related toxicity & Management

An Anecdote: Patient AR

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Immune related toxicities: what

Hypophysitis

Thyroiditis

Adrenal

Insufficiency

Enterocolitis

Dermatitis

Pneumonitis

Hepatitis

Pancreatitis

Neuropathy

Arthritis

• Any organ!

• Distinct mechanism of

action

• May be exacerbated by

underlying autoimmune

conditions/presence of

autoantibodies

Boutros et al, Nat Rev Oncol 2016

Immune related toxicities: what

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Boutros et al, Nat Rev Oncol 2016

Immune related toxicities: what

Immune related toxicities: when?

Weber et al, JCO 2012; Antonia et al, ESMO 2015

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Immune related toxicities: general management

Principles for the generalist

1) Always suspect immune-

related toxicity

2) Rule out common causes

3) Seek confirmatory diagnosis

4) Grade toxicity and utilize

algorithms

5) Oncology consult ���� clinical

trials implications

Grade 1Grade 1Grade 1Grade 1: - Supportive care

- Consider drug withhold

Grade 2Grade 2Grade 2Grade 2:

- Withhold drug.

- Low-dose corticosteroids

(prednisone 0.5-1mg/kg/day or equivalent).

- Consider re-dose if toxicity resolves to

≤ Grade 1.

Grade 3Grade 3Grade 3Grade 3----4444: - Discontinue drug.

- High-dose corticosteroids

- (prednisone 1-2mg/kg/day or equivalent)

tapered over ≥ 1 month once toxicity

resolves to ≤ Grade 1.

Immune related toxicities: colitis

Diagnostic WorkupDiagnostic WorkupDiagnostic WorkupDiagnostic Workup

- Rule out alternative diagnosis:

C.difficile, other GI infections

- Distinguish between diarrhea and

colitis

- Consider invasive testing with

colonoscopy

ManagementManagementManagementManagement

- Low threshold for starting

corticosteroids

- No benefit for corticosteroid pre-

treatment (budesonide)

- Colitis that is slow to

improve/refractory to steroids: treat

with anti-TNF

- Infliximab 5mg once or twice every

14 days

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Toxicities: Pneumonitis

Toxicities: Pneumonitis

Hypersensitivity

COP-like

GGO

Interstitial

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Toxicities: Pneumonitis

Naidoo et al, JCO 2016

Pneumonitis Management Algorithm

Grade Investigations Management Follow-up

1Asymptomatic,

Radiologic changes

only

2Mild/moderate new

symptoms

3-4Severe/life-threatening

new symptoms or

worsening hypoxia

• Radiologic

imaging

(High resolution

CT chest)

• Microbial

assessment where

necessary

• Consider

Pulmonary/Infecti

ous Diseases

Consults and

Bronchoscopy

• Withhold immunotherapy

• Monitor for symptoms daily

• Oral prednisone 1mg/kg/day or

equivalent

• Continue immunotherapy

• Monitor for symptoms every 3

days

• Discontinue immunotherapy

• Hospitalization

• IV methylprednisolone

2-4mg/kg/day or equivalent

• Prophylactic antibiotics

• Repeat CT every cycle

• If develops symptoms, treat as

higher grade

• If improves to ≤Grade 1 within 3

days of supportive care, resume

immunotherapy at next dose

• If persistent beyond 3 days,

discontinue immunotherapy

• After symptoms improve, taper

steroids over ≥1 month

• After symptoms improve to

≤Grade 1 or baseline, taper

steroids over ≥6 weeks

• If worsens in 48 hours consider

additional immunosuppression

(infliximab, cyclophosphamide,

mycophenolate mofetil)

Naidoo et al, JCO 2016

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Profound Fatigue

Think endocrine!

PituitaryHypophysitis

ThyroidThyroiditis

AdrenalInsufficiency

Consider MRI pituitary protocol

TSH, FT4 +/- T3

Cortisol, ACTH Stim

***Check serially!

Treatment:

Hormone Replacement

Endocrinology Consultation

Profound Fatigue

Think endocrine!

PituitaryHypophysitis

ThyroidThyroiditis

AdrenalInsufficiency

Consider MRI pituitary protocol

Serial TSH, FT4 +/- T3

Cortisol, ACTH Stim

***Check serially!

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Toxicities: Rash

Maculopapular Papulopustular Sweet’s syndrome

Lichenoid DermatitisBullous Pemphigoid

Toxicities: Rash

Maculopapular Papulopustular Sweet’s syndrome

Lichenoid DermatitisBullous Pemphigoid

All of the above!

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Toxicities: Rash

Maculopapular Papulopustular

Bullous Pemphigoid

20-40% Patients with anti-PD-1

Rarely serious, <5% Tx d/c rate

Management:

• Mild, <10% BSA: topical steroid

• 10-30% BSA: oral steroid, hold Tx

• >30% BSA or severe� derm

consult

Antibody mediated (against BP180)

Also found on melanomas

• Presentation

- Mainly asymptomatic elevations in AST/ALT

- 10% with anti-CTLA4 mAb

- <5% with anti-PD-1/PD-L1 mAb

- Grade 3+ events: 1-2%

- Increased toxicity with combinations (vemurafenib)

• Management

- Minimize alcohol intake

- Oral steroid taper of at least 3 weeks

- *No infliximab* (FDA Blackbox warning)

- Mycophenolate 500mg-1000mg bid

Toxicities: Immune Related Hepatitis

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Can you treat a patient with prior autoimmune conditions?

Yes!

Anti-PD-1 JHU cohort:

52 patients with previous autoimmune disease

• 38% had mild flare of prior condition;

• 4% required discontinuation;

• 29% developed other irAEs, 8% requiring discontinuation

Can you treat a patient with prior autoimmune conditions?

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Agenda

Immune related response criteria & implications

Nishino M et al, Nature Reviews Clin Oncology 2017

Agenda: Future Directions

IL-2 + SBRT

Pegylated IL-2

Intramammary IRX

Anti-OX40

Anti-PD-1 + Chemotherapy

Anti-TGFb+

Radiotherapy

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Thank you!